Mammalian development begins with a single totipoitent cell that undergoes an ordered process of differentiation to form a complex multicellular organism. During embryogenesis the ventral mesoderm is the origin for the both the hematopoietic and circulatory systems. Indeed a pluripotent progenitor - named the hemangioblast has been defined in the embryo that is capable of differentiating into both the blood and blood vessels. The hematopoietic stem cell (HSC) may be originally derived from the embryonic hemangioblast or it may arise separately. HSC are defined by their ability to self renew and to generate all of the cells of the blood and lymph. The classic assay for HSC function is reconstitution of the hematopoietic system in an lethally irradiated animal. HSC self renewal can be demonstrated by serial reconstitution of irradiated hosts (43). The ability of a single HSC clone to perform all of these tasks was proven by showing that all the blood cell lineages of mice transplanted with retrovirally tagged HSC carried the same tag (30). A recent flurry of experiments has revealed the "plasticity" of HSC by showing their ability to differentiate into many non-hematopoietic lineages (26, 35, 51).We recently developed a mouse model of retinal neovascularization that mimics many features of human disease. A series of experiments was designed to ask if adult HSC exhibit hemangioblast activity by contributing to both blood and neovascularization of remote tissues in response to ischemic injury. Bone marrow transplant recipients were durably reconstituted with donor HSC from congenic mice expressing gfp. Ischemia was induced in one retina per animal. Physiological localization of marrow-derived progeny to retina was detected by confocal microscopy of newly differentiated vascular tufts made of gfp+ endothelial cells. Both FACS and fluorescent microscopy confirmed full multilineage hematopoietic reconstitution of the transplant recipients. These studies demonstrate for the first time that adult HSC exhibit a functional "hemangioblast" activity leading to the development of both blood and vascular endothelial cells. Furthermore, serial transplants confirmed that "hemangioblast" activity co-enriches with the HSC, as defined by the concurrent ability to self renew and durably reconstitute multilineage hematopoiesis. In this proposal we seek to utilize this unique model to address the following hypotheses: Aim 1. Hypothesis: HSC contribution to both the blood and vascular endothelium is derived from a single clone exhibiting true hemangioblast activity. Aim 2. Hypothesis: Adult stem cells from the liver and brain exhibit similar differentiative "plasticity" as the HSC. Therefore, both LSC and NSC can be induced to regenerate vascular endothelium. Aim 3. Hypothesis: HSC transplant can be utilized to repair retinal ischemia via beneficial intraretinal neovascularization without inducing vision damaging preretinal neovascularization.